Novel crystalline polymorph of venlafaxine hydrochloride and methods for the preparation thereof

ABSTRACT

This invention relates to a highly thermally stable novel anhydrous crystalline polymorphic form of venlafaxine hydrochloride, methods for the preparation thereof, and its use.

This application is a divisional of copending U.S. application Ser. No.10/308,480, filed on Dec. 3, 2002, which claims benefit to ProvisionalApplication No. 60/335,822, filed on Dec. 5, 2001, the entire disclosureof which is hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to a novel highly thermally stable anhydrouscrystalline polymorphic form of venlafaxine hydrochloride, methods forthe preparation thereof, and its use.

BACKGROUND OF THE INVENTION

Venlafaxine (1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol)and its therapeutically acceptable salts (collectively referred to asvenlafaxine herein) are inhibitors of monoamine neurotransmitter uptake,a mechanism associated with clinical antidepressant activity. Thismechanism has also been associated with reproductive function byaffecting indirectly the hypothalamic-pituitary-ovarian axis. It isbelieved that venlafaxine's mechanism of action is related to potentinhibition of the uptake of the monoamine neurotransmitters serotoninand norepinephrine. To a lesser degree, venlafaxine also inhibitsdopamine reuptake. However, it has no inhibitory activity on monoamineoxidase.

In contrast to classical tricyclic antidepressant drugs, venlafaxine hasvirtually no affinity for muscaranic, histaminergic, or adrenergicreceptors in vitro. Pharmacologic activity at these receptors isassociated with the various anticholinergic, sedative, andcardiovascular effects seen with the tricyclic antidepressant drugs.

Hypothalamic amenorrhea in depressed and non-depressed human females mayalso be treated with venlafaxine as taught in U.S. Pat. No. 5,506,270.

U.S. Pat. No. 5,530,013 teaches that venlafaxine induces cognitionenhancement and treats cognitive impairment in a mammal.

U.S. Pat. No. 5,744,474 discloses that venlafaxine can treat urinaryincontinence in humans.

More recently, as discussed in U.S. Pat. No. 5,916,923, venlafaxine hasbeen found to treat, prevent, and control obesity, generalized anxietydisorder, post-traumatic stress disorder, late luteal phase disphoricdisorder (premenstrual syndrome), attention deficit disorder (with andwithout hyperactivity), Gilles de la Tourette syndrome, bulimia nervosa,and Shy Drager Syndrome in mammals (e.g., humans).

Extended release formulations of venlafaxine are disclosed in U.S. Pat.No. 6,274,171 and International Patent Publication No. WO 94/27589. Asdiscussed in U.S. Pat. No. 6,274,171, venlafaxine hydrochloride is knownto exist in two polymorphic forms, Forms I and II. Characteristic X-raypowder diffraction patterns for Forms I and II are shown in FIGS. 2 and3, respectively.

SUMMARY OF THE INVENTION

The present invention provides a novel anhydrous crystalline polymorphof venlafaxine hydrochloride. This crystalline polymorph is morethermally stable than known forms of venlafaxine hydrochloride. Whileforms I and II of venlafaxine hydrochloride have melting points of 209and 211° C. ΔH=125.8 and 130.3 J/g), respectively, the melting point ofthe crystalline polymorph of the present invention is about 219° C.ΔH=116 J/g). Because of this stability, a mixture of various polymorphsof venlafaxine hydrochloride can be formed into a pure form of this newpolymorph. Furthermore, residual solvents used in the preparation ofthis new polymorph or the precursor venlafaxine hydrochloride can beeasily removed.

The crystalline polymorph of the present invention exhibitscharacteristic XRPD peaks (expressed in degrees 2θ) at about 5.67, 7.28,9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81, 16.17,16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74, 21.86, 22.33,22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62, 26.97, 27.64, 28.25,29.01, 29.96, 31.01, 31.61, 32.75, 34.54, 35.50, 35.95 and 36.91.

The crystalline polymorph of the present invention can be administeredto a mammal to treat depression (including, but not limited to, majordepressive disorder, bipolar disorder, and dysthymia), fibromyalgia,anxiety, panic disorder, agorophobia, post traumatic stress disorder,premenstrual dysphoric disorder (premenstrual syndrome), attentiondeficit disorder (with and without hyperactivity), obsessive compulsivedisorder (including trichotillomania), social anxiety disorder,generalized anxiety disorder, autism, schizophrenia, obesity, anorexianervosa, bulimia nervosa, Gilles de la Tourette Syndrome, vasomotorflushing, cocaine and alcohol addiction, sexual dysfunction (includingpremature ejaculation), borderline personality disorder, chronic fatiguesyndrome, urinary incontinence, pain (including, but not limited to,migraine, chronic back pain, phantom limb pain, central pain,neuropathic pain such as diabetic neuropathy, and postherpeticneuropathy), Shy Drager Syndrome, or Raynaud's syndrome. The crystallinepolymorph can also be administered to prevent relapse or recurrence ofdepression, to induce cognitive enhancement, to treat cognitiveimpairment, and in regimens for cessation of smoking or other tobaccouses. Additionally, the crystalline polymorph can be administered totreat hypothalamic amenorrhea in depressed and non-depressed humanfemales. These methods involve administering to a mammal (e.g., a human)in need thereof an effective amount of the crystalline polymorph of thepresent invention or a mixture of venlafaxine polymorphs that containsthe crystalline polymorph of the present invention. Preferably, thevenlafaxine is administered orally.

Another embodiment is a pharmaceutical composition comprising thecrystalline polymorph of the present invention and, optionally, apharmaceutically acceptable carrier or diluent. Typically, thepharmaceutical composition comprises an amount of the crystallinepolymorph effective to treat depression or any of the aforementionedindications in an animal, such as a mammal (e.g. human). According toone preferred embodiment, the pharmaceutical composition comprises atleast about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1,99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of thecrystalline polymorph of the present invention, based upon 100% totalweight of venlafaxine hydrochloride in the pharmaceutical composition.According to another preferred embodiment, the pharmaceuticalcomposition comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95,96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%by weight of the crystalline polymorph of the present invention, basedupon 100% total weight of venlafaxine hydrochloride in thepharmaceutical composition.

The pharmaceutical composition may be incorporated into a dosage form,such as a tablet or capsule.

The crystalline polymorph of the present invention can be prepared byheating venlafaxine hydrochloride of form I or II or mixtures thereof toa temperature of at least about 197° C. and more preferably at leastabout 200° C. According to one embodiment, the venlafaxine hydrochlorideis heated to about 200° C. Generally, the venlafaxine hydrochloride isheated for at least about 60 minutes and more preferably for at leastabout 150 minutes. The crystals formed may be recovered by any methodknown in the art.

Another embodiment is a method of preparing a substantially purecrystalline polymorphic form of venlafaxine hydrochloride. The methodincludes obtaining the venlafaxine hydrochloride crystalline polymorphof the present invention in substantially pure form and then convertingthe substantially pure venlafaxine hydrochloride into anotherpolymorphic form, such as form I. The substantially pure venlafaxinehydrochloride product can be incorporated into pharmaceuticalcompositions and dosage forms as known in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic X-ray Powder Diffraction (XRPD) pattern ofthe anhydrous venlafaxine hydrochloride crystalline polymorph of thepresent invention.

FIG. 2 is a characteristic XRPD pattern of Form I of venlafaxinehydrochloride.

FIG. 3 is a characteristic XRPD pattern of Form II of venlafaxinehydrochloride.

FIG. 4 is a differential scanning calorimetry (DSC) scan of theanhydrous venlafaxine hydrochloride crystalline polymorph of the presentinvention carried out in a sealed pan at a scan rate of 10° C./minutefrom 25 to 240° C. under a nitrogen purge.

FIG. 5 is a thermogravimetric analysis (TGA) of the anhydrouscrystalline polymorph of the present invention heated from 28 to 238° C.at a scan rate of 10° C./minute under a nitrogen purge.

DETAILED DESCRIPTION OF THE INVENTION

The term “about” generally means within 10%, preferably within 5%, andmore preferably within 1% of a given value or range. With regard to agiven value or range in degrees 22 from XRPD patterns, the term “about”generally means within 0.2° 2θ and preferably within 0.10, 0.05°, or0.01° 2θ of the given value or range. Alternatively, the term “about”means within an acceptable standard error of the mean, when consideredby one of ordinary skill in the art.

The term “treat” as used herein refers to preventing, ameliorating,controlling, or curing the desired symptoms or disorders.

The term “venlafaxine hydrochloride” as used herein refers to racemicmixtures of R and S-venlafaxine and their optically pure enantiomers.The crystalline polymorph of the present invention may be R, S, or aracemic mixture of R and S-venlafaxine hydrochloride.

The crystalline polymorph has an XRPD pattern substantially identical tothat shown in FIG. 1. Peak locations and intensities for the XRPDpattern in FIG. 1 are provided in Table 1 below. TABLE 1 CharacteristicXRPD Peaks (expressed in degrees 2θ) D-spacing in Angstrom (Å) andIntensities of Diffraction Lines in CPS for the Polymorphic Form ofVenlafaxine Hydrochloride Degrees 2θ d (Å) I (Counts per Second (CPS)5.67 15.57 309.09 7.28 12.14 828.73 9.14 9.67 766.93 9.67 9.14 262.2610.77 8.21 303.39 11.31 7.82 728.55 14.01 6.31 224.07 14.54 6.09 807.8714.85 5.96 887.19 15.48 5.72 830.41 15.81 5.60 617.50 16.17 5.48 357.3316.94 5.23 728.55 17.68 5.01 338.29 18.02 4.92 312.91 18.48 4.80 753.9319.29 4.60 1069.82 19.69 4.50 963.51 20.46 4.34 866.61 20.74 4.281084.34 21.86 4.06 365.61 22.33 3.98 187.75 22.67 3.92 259.14 22.95 3.87240.39 23.17 3.84 343.83 24.06 3.70 264.69 24.61 3.62 403.19 25.13 3.54498.24 26.62 3.35 479.23 26.97 3.30 783.01 27.64 3.23 338.01 28.25 3.16294.56 29.01 3.08 452.07 29.96 2.98 237.53 31.01 2.88 348.88 31.61 2.83478.42 32.75 2.73 332.38 34.54 2.60 347.78 35.50 2.53 338.55 35.95 2.50315.92 36.91 2.43 221.30In particular, the peaks (expressed in degrees 2θ) at about 5.67, 7.28,9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74 are unique tothis crystalline polymorph. The crystalline polymorph also has a meltingendotherm, according to differential scanning calorimetry, at 219° C.

The crystalline polymorph of the present invention is useful fortreating, preventing, or controlling depression and the aforementionedindications. The appropriate dosage amounts for an animal can bedetermined by methods known in the art. Generally, a therapeuticeffective amount for the desired purpose is administered. The dosage ofthe crystalline polymorph of venlafaxine hydrochloride disclosed hereinis generally from about 75 to about 300 mg per day.

The crystalline polymorph can be formulated into a pharmaceuticalcomposition. Preferably, the pharmaceutical composition comprises anamount of the crystalline polymorph of venlafaxine hydrochlorideeffective to treat the desired indication in an animal, such as a human.According to one preferred embodiment, the pharmaceutical compositioncomprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98,99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weightof the crystalline polymorph of venlafaxine hydrochloride, based upon100% total weight of venlafaxine hydrochloride in the pharmaceuticalcomposition. According to another embodiment, the pharmaceuticalcomposition comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95,96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%by weight of the crystalline polymorph of venlafaxine hydrochloride,based upon 100% total weight of crystalline venlafaxine hydrochloride inthe pharmaceutical composition.

The pharmaceutical composition can also be substantially free orcompletely free of other crystalline polymorphs of venlafaxinehydrochloride, such as Forms I and II. The terms “substantially free”and “substantially pure” include those pharmaceutical compositions thatcontain less than 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1 or 2% by weight ofother crystalline polymorphs, such as Form I or II or both, based uponthe total weight of pharmaceutical composition (or alternatively basedupon on the total weight of venlafaxine hydrochloride in thepharmaceutical composition).

According to one embodiment, the pharmaceutical composition containsfrom about 25 to about 350 mg of the crystalline polymorph ofvenlafaxine hydrochloride. More preferably, pharmaceutical compositionsof the present invention contain 75 mg, 150 mg or 225 mg of thecrystalline polymorph of venlafaxine hydrochloride.

The pharmaceutical composition may also include one or morepharmaceutically acceptable carriers or diluents and excipients. Theterm “excipient” includes, but is not limited to, those materials thatare acceptable for use in pharmaceutical formulations, and are added tothe formulation to promote the stability and viability of theformulation, such as binders, bulking agents, clarifying agents,buffering agents, wetting agents, lubricants, sweeteners, and flavoringagents. Suitable excipients include, but are not limited to, cellulose,ethyl cellulose, gelatin, hydroxypropyl methylcellulose, iron oxide,titanium dioxide, lactose, magnesium stearate, and sodium starchglycolate. Suitable pharmaceutically acceptable carriers, diluents, andexcipients also include those described in Remington's, The Science andPractice of Pharmacy, (Gennaro, A. R., ed., 19^(th) edition, 1995, MackPub. Co.) which is herein incorporated by reference. The phrase“pharmaceutically acceptable” refers to additives or compositions thatare physiologically tolerable and do not typically produce an allergicor similar untoward reaction, such as gastric upset, dizziness and thelike, when administered to an animal, such as a mammal (e.g. a human).

According to one preferred embodiment, the pharmaceutical composition isan extended release formulation, such as that described in U.S. Pat. No.6,274,171, which is herein incorporated by reference. For example, anextended release formulation may comprise spheroids comprised of thecrystalline polymorph of the present invention, microcrystallinecellulose, and, optionally, hydroxypropyl-methylcellulose. The spheroidsare preferably coated with a film coating composition comprised of ethylcellulose and hydroxypropylmethylcellulose.

The pharmaceutical composition may be a dosage form, such as a liquid(e.g., elixirs and suspensions), capsule, pill, or tablet. Thepharmaceutical compositions and the crystalline polymorph of venlafaxinehydrochloride may be administered to animals, including, but not limitedto, mammals (e.g. humans), orally, intravenously, intramuscularly,parenterally intraperitoneally, subdermally, buccally, subcutaneously,transdermally, topically, rectally, vaginally, or intranasally.Preferably, the composition is administered orally.

The crystalline polymorph of the present invention can be prepared byheating venlafaxine hydrochloride of form I or II or mixtures thereof toat least about 197° C. and more preferably at least about 200° C.According to one embodiment, the venlafaxine hydrochloride is heated toabout 200° C. Generally, the venlafaxine hydrochloride is heated for atime sufficient to form the crystalline polymorph of the presentinvention. Preferably, the venlafaxine hydrochloride precursor is heatedfor at least about 60 minutes and more preferably for at least about 150minutes. The crystalline polymorph may be prepared in substantially pureform by heating the venlafaxine hydrochloride precursor for a sufficientamount of time.

Venlafaxine hydrochloride may be prepared by any method known in the artincluding, but not limited to, the methods described in U.S. Pat. Nos.4,535,186 and 4,761,501 and International Patent Publication Nos. WO00/32555, WO 00/32556, and WO 01/07397, all of which are herebyincorporated by reference.

The crystals formed may be recovered by any method known in the art,such as filtration, centrifugation, or with a Buchner style filter,Rosenmund filter, or plates and frame press. Typically, the crystals arerecovered as solids.

The crystalline polymorph can be converted into Form I byrecrystallizing it in ethyl acetate in ethanol (e.g., 80% ethyl acetatein ethanol).

As discussed above, substantially pure forms of the crystallinepolymorph can be prepared such as by heating one or more forms ofvenlafaxine hydrochloride to about 200° C. for a sufficient time. Thesubstantially pure crystalline polymorph can be used to prepare othersubstantially pure crystalline polymorphic forms of venlafaxinehydrochloride, such as form I, by the methods described above. Thesubstantially pure venlafaxine hydrochloride product can be incorporatedinto pharmaceutical compositions and dosage forms as known in the art.

EXAMPLES

The following examples are illustrative and are not meant to limit thescope of the claimed invention. The venlafaxine hydrochloride which isused as a raw material in the example below can be prepared by anymethod known in the art.

Example 1 Preparation of Anhydrous Venlafaxine Hydrochloride

About 100 mg of venlafaxine hydrochloride of Form II was put in a glassvial, flushed with nitrogen gas and then sealed by heat. The sealed vialwas put in an oil bath at about 200° C. (197° C. to 200° C.) for 1 houror until the shape of the crystals changed to form cream-white crystals.

Example 2 Preparation of Anhydrous Venlafaxine Hydrochloride

The procedure in Example 1 was repeated with 500 mg of venlafaxinehydrochloride of Form II, except the vial was left in the oil bath for2.5 hours instead of 1 hour.

Example 3 Preparation of Anhydrous Venlafaxine Hydrochloride

The procedure in Example 1 was repeated, except an aluminum vial wasused instead of a glass vial.

Example 4 X-ray Powder Diffraction (XRPD)

XRPD was performed on the crystalline polymorph of venlafaxinehydrochloride of the present invention under dry conditions with aScintag X2 X-Ray Diffraction System Model 00-A02, available from ThermoARL of Ecublens, Switzerland. The XRPD instrument had the followingparameters: Scan Type: Normal Start Angle: 3 degrees Stop Angle: 40degrees Number of Points: 1851 points Step Size: 0.02 degrees DatafileResolution: 1600 Scan Rate: 0.04 Scan Mode: Step Wavelength: 1.540562Diffraction Optics: Detector: Type: Fixed Slits X2 Configuration: NoTube: Type: Fixed Slits X2 Configuration: NoThe results are shown in FIG. 1.

This procedure was repeated for Forms I and II of venlafaxinehydrochloride. The results for Forms I and II are shown in FIGS. 2 and3, respectively.

Example 5 Intrinsic Dissolution Rate

The intrinsic dissolution rates of Form II and the crystalline polymorphof the present invention were determined as follows. Pellets ofvenlafaxine hydrochloride were prepared by compressing 100 mg of eachmaterial in a die (Wood's apparatus) at 1000 psi for 1 minute with aCarver press. The pellets produced were then fitted into a dissolutionapparatus (Vankel 7010 equipped with a Cary 300 Ultraviolet/VisibleSpectrophotometer) which resulted in a single exposed surface area of0.5 cm². The dissolution rate in 900 mL of water was determined by USP23 (1995), section 711, page 1791 (Dissolution, apparatus 2), with arotation speed of 100 rpm at 37° C. The dissolution media was circulatedthrough a 1.0 cm path microflow cell at a flow rate of 10 mL/minute.Ultraviolet absorbance was recorded at 220 nm.

Both Form II and the crystalline polymorph of the present inventionexhibited dissolution rates of 24.7 mg/cm²-minute.

Example 6 Differential Scanning Calorimetry (DSC)

DSC measurements on the anhydrous venlafaxine hydrochloride crystallinepolymorph of the present invention were carried out in a sealed pan at ascan rate of 10° C./minute from 25° C. to 240° C. under a nitrogen purgewith a Pyris I DSC available from Perkin-Elmer of Shelton, Conn. The DSCscan is shown in FIG. 4.

FIG. 4 shows one endotherm at 221° C. (heat of fusion is 116 J/g), whichwas the melting of the anhydrous venlafaxine hydrochloride. The onsetmelting temperature for the venlafaxine hydrochloride was 219° C.

Example 7 Thermogravimetric Analysis (TGA)

A sample of the venlafaxine hydrochloride crystalline polymorph of thepresent invention was heated from 28 to 238° C. at a scan rate of 10°C./minute in a Pyris I TGA, available from Perkin-Elmer of Shelton,Conn., under a nitrogen purge. The results are shown in FIG. 5. Thesample lost little weight until it was heated near the melting point ofvenlafaxine hydrochloride.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims. It is further to be understood that valuesare approximate, and are provided for description.

Patents, patent applications, publications, procedures, and the like arecited throughout this application, the disclosures of which areincorporated herein by reference in their entireties. To the extent thata conflict may exist between the specification and a reference, thelanguage of the disclosure made herein controls.

1. A method of treating depression in a mammal in need thereofcomprising administering to the mammal an effective amount of acrystalline polymorph of venlafaxine hydrochloride exhibiting an X-raypowder diffraction pattern having characteristic peaks expressed indegrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17,19.69, and 20.74.
 2. A method of treating generalized anxiety disorderin a mammal in need thereof comprising administering to the mammal aneffective amount of a crystalline polymorph of venlafaxine hydrochlorideexhibiting an X-ray powder diffraction pattern having characteristicpeaks expressed in degrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77,14.01, 14.54, 16.17, 19.69, and 20.74.
 3. A method of treating socialanxiety disorder in a mammal in need thereof comprising administering tothe mammal an effective amount of a crystalline polymorph of venlafaxinehydrochloride exhibiting an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ at about 5.67, 7.28, 9.14,9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
 4. A method oftreating post traumatic stress disorder in a mammal in need thereofcomprising administering to the mammal an effective amount of acrystalline polymorph of venlafaxine hydrochloride exhibiting an X-raypowder diffraction pattern having characteristic peaks expressed indegrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17,19.69, and 20.74.
 5. A method of treating panic disorder in a mammal inneed thereof comprising administering to the mammal an effective amountof a crystalline polymorph of venlafaxine hydrochloride exhibiting anX-ray powder diffraction pattern having characteristic peaks expressedin degrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54,16.17, 19.69, and 20.74.
 6. A method of preventing relapse or recurrenceof depression disorder in a mammal in need thereof comprisingadministering to the mammal an effective amount of a crystallinepolymorph of venlafaxine hydrochloride exhibiting an X-ray powderdiffraction pattern having characteristic peaks expressed in degrees 2θat about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and20.74.
 7. A method of treating depression, generalized anxiety disorder,social anxiety disorder, post traumatic stress disorder or panicdisorder, or preventing the relapse or recurrence of depression,comprising administering to a mammal in need thereof an effective amountof a crystalline polymorph of venlafaxine hydrochloride exhibiting anX-ray powder diffraction pattern having characteristic peaks expressedin degrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77, 11.31, 14.01,14.54, 14.85, 15.48, 15.81, 16.17, 16.94, 17.68, 18.02, 18.48, 19.29,19.69, 20.46, 20.74, 21.86, 22.33, 22.67, 22.95, 23.17, 24.06, 24.61,25.13, 26.62, 26.97, 27.64, 28.25, 29.01, 29.96, 31.01, 31.61, 32.75,34.54, 35.50, 35.95 and 36.91.
 8. A method of treating depression,generalized anxiety disorder, social anxiety disorder, post traumaticstress disorder or panic disorder, or preventing the relapse orrecurrence of depression, comprising administering to a mammal in needthereof an effective amount of a crystalline polymorph of venlafaxinehydrochloride having an X-ray powder diffraction pattern substantiallythe same as that shown in FIG.
 1. 9. A method of treating depression,generalized anxiety disorder, social anxiety disorder, post traumaticstress disorder or panic disorder, or preventing the relapse orrecurrence of depression, comprising administering to a mammal in needthereof an effective amount of substantially pure anhydrous venlafaxinehydrochloride.
 10. The method of claim 9 wherein the anhydrousvenlafaxine hydrochloride has a melting point of about 219° C. 11.Substantially pure anhydrous venlafaxine hydrochloride.
 12. A method ofpreparing anhydrous venlafaxine hydrochloride, the method comprisingheating form I or II of venlafaxine hydrochloride or a mixture thereofto at least about 197° C. for a time sufficient to form the anhydrousvenlafaxine hydrochloride.
 13. The method of claim 12, wherein thevenlafaxine hydrochloride is heated to at least about 200° C.
 14. Themethod of claim 12, wherein the venlafaxine hydrochloride is heated forat least about 60 minutes.
 15. The method of claim 13, wherein thevenlafaxine hydrochloride is heated for at least 150 minutes.
 16. Themethod of claim 12 wherein the anhydrous venlafaxine hydrochlorideexhibits an X-ray powder diffraction pattern having characteristic peaksexpressed in degrees 2θ at about 5.67, 7.28, 9.14, 9.67, 10.77, 14.01,14.54, 16.17, 19.69, and 20.74.
 17. The method of claim 12 wherein theanhydrous venlafaxine hydrochloride exhibits an X-ray powder diffractionpattern having characteristic peaks expressed in degrees 2θ at about5.67, 7.28, 9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81,16.17, 16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74, 21.86,22.33, 22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62, 26.97, 27.64,28.25, 29.01, 29.96, 31.01, 31.61, 32.75, 34.54, 35.50, 35.95 and 36.91.18. The method of claim 12 wherein the anhydrous venlafaxinehydrochloride exhibits an X-ray powder diffraction pattern substantiallyas that shown in FIG.
 1. 19. The method of claim 12 wherein theanhydrous venlafaxine is substantially pure.
 20. Anhydrous venlafaxinehydrochloride prepared according to claim
 12. 21. Anhydrous venlafaxinehydrochloride prepared according to claim 20 which is substantiallypure.
 22. Anhydrous venlafaxine hydrochloride prepared according toclaim 12 having a melting point of
 219. 23. Anhydrous venlafaxinehydrochloride prepared according to claim 22 which is substantiallypure.
 24. Anhydrous venlafaxine hydrochloride prepared according toclaim 12 exhibiting an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ at about 5.67, 7.28, 9.14,9.67, 10.77, 14.01, 14.54, 16.17, 19.69, and 20.74.
 25. Anhydrousvenlafaxine hydrochloride prepared according to claim 24 which issubstantially pure.
 26. Anhydrous venlafaxine hydrochloride preparedaccording to claim 12 exhibiting an X-ray powder diffraction patternhaving characteristic peaks expressed in degrees 2θ at about 5.67, 7.28,9.14, 9.67, 10.77, 11.31, 14.01, 14.54, 14.85, 15.48, 15.81, 16.17,16.94, 17.68, 18.02, 18.48, 19.29, 19.69, 20.46, 20.74, 21.86, 22.33,22.67, 22.95, 23.17, 24.06, 24.61, 25.13, 26.62, 26.97, 27.64, 28.25,29.01, 29.96, 31.01, 31.61, 32.75, 34.54, 35.50, 35.95 and 36.91. 27.Anhydrous venlafaxine hydrochloride prepared according to claim 26 whichis substantially pure.
 28. Anhydrous venlafaxine hydrochloride preparedaccording to claim 12 exhibiting an X-ray powder diffraction patternsubstantially as that shown in FIG.
 1. 29. Substantially pure anhydrousvenlafaxine hydrochloride prepared according to claim 12 exhibiting anX-ray powder diffraction pattern substantially as that shown in FIG. 1.30. A method of preparing a crystalline polymorph of venlafaxinehydrochloride in substantially pure form, the method comprising: (a)obtaining venlafaxine hydrochloride having an X-ray powder diffractionpattern substantially the same as that shown in FIG. 1 in substantiallypure form; and (b) converting the venlafaxine hydrochloride of step (a)into a different crystalline polymorphic form.
 31. The method of claim30, wherein the venlafaxine hydrochloride formed in step (b) is Form Iof venlafaxine hydrochloride.
 32. The method of claim 30 wherein thevenlafaxine hydrochloride formed in step (b) is Form II of venlafaxinehydrochloride.